Synapse remodeling is the process of forming and eliminating synapses to reorganize the existing brain circuitry, and is indispensable for establishing and maintaining the integrity of the nervous system. Synapses are constantly remodeled throughout the lifetime of an animal. Remodeling peaks in the juvenile nervous system, levels off throughout adulthood, and declines with senescence. The long-term goal of my research is to identify the signaling pathways and molecular machinery that mediate synapse remodeling. This will help us to understand how synapses are formed and eliminated at the right time and right place, and provide fundamental information towards our ultimate goal of understanding and treating numerous neurological diseases and mental disorders. To approach analysis of synapse remodeling at the molecular level, it is informative to begin with a simple invertebrate model. In C. elegans, synapse remodeling occurs in a reliable and predictable manner during development. At the end of the first larval stage, 6 motor neurons reverse their axon-dendrite polarity, disassemble existing synapses, and form new ones in a distant location. This simple rewiring process provides an excellent model system that is accessible to both molecular manipulation and in vivo optical observation. The objective of my proposed research is to investigate the molecular pathways defining the timing of synapse remodeling and to identify new genes involved in switching the identity of the synapses. This application includes the following aims: first, I will investigate temporal regulation of synapse remodeling, testing the hypothesis that genes responsible for controlling the sequence of developmental events (heterochronic genes) regulate synapse remodeling. Second, I will combine data from microarray analysis, a RNAi screen and a forward genetic screen to identify new factors required for synapse remodeling. Finally, a novel quantitative imaging analysis approach will be used to determine spatial regulation of the ubiquitin-proteasome system mediating degradation of synaptic components during synapse remodeling. Together, the experiments outlined in this application will provide a mechanistic understanding of synapse remodeling and its regulation.